The goal of this proposal is to identify genes that contribute to cardiovascular disease (CVD) in people with diabetes. Diabetes is a profound influence on CVD development. The focus of this study is subclinical measures of CVD: vascular calcified plaque and carotid atherosclerosis. In the first phase of the Diabetes Heart Study we successfully recruited and extensively phenotyped 1443 subjects in 564 families with multiple type 2 diabetes (T2DM) affected subjects. This created a unique data resource for the study of CVD and other related traits in a diabetes-enriched (85%) population. Extensive genetic and epidemiological analyses were performed. These results provide a strong foundation for the proposed identification of important genes using a Genome Wide Association Study (GWAS) approach. Specific Aims are: 1). GWAS genotyping and analysis of subjects from the Diabetes Heart Study. The entire European American sample will be genotyped on the Affymetrix SNP Array 6.0 platform. A comprehensive analysis of the genotypic data will be carried out to identify loci/genes associated with the primary measures of subclinical CVD of vascular calcified plaque and carotid wall thickness. 2). Replication and meta analyses of coronary calcified plaque and carotid wall thickness. A meta analysis of European American samples with GWAS data for coronary calcified plaque and, where possible, carotid wall thickness, will be performed in the Framingham Heart Study, Genetic Epidemiology Network of Arteriopathy (GENOA), Amish Family Calcification Study (AFCS), and the Diabetes Heart Study. 3). High scoring polymorphisms from Aims 2 will be evaluated for replication in other study samples to further test for association with: a) prevalent CVD in European Americans, b) subclinical CVD in other ethnicities/races, and c) prevalent CVD in other ethnicities/races. 4). Intensive molecular genetic analysis, novel analytic, and bioinformatic approaches will be used to identify trait influencing variants. The best replicated loci from the Aims 2 &3 will be subjected to additional genotyping (if appropriate) and resequencing to clearly define risk loci. Innovative analysis approaches will be used to define trait associated variants. We have assembled an experienced, highly productive, interdisciplinary team to perform this promising study. PUBLIC HEALTH RELEVANCE: In this research study, genes which contribute to heart disease in people with diabetes will be identified.